Process for the preparation of dronedarone

ABSTRACT

The present invention provides, according to an aspect thereof, a novel process for the preparation of dronedarone [1] and pharmaceutically acceptable salts thereof. According to a preferred embodiment, the process comprises N-acetylating of p-anisidine or p-phenetidine with acetic anhydride, reacting of the obtained N-(4-alkoxyphenyl)acetamide with 2-bromohexanoyl chloride or bromide in the presence of aluminum chloride or bromide to obtain N-[3-(2-bromohexanoyl)-4-hydroxyphenyl]acetamide [6 a ], converting the compound [6 a ] into 2-butyl-5-benzofuranamine hydrochloride [12 a ] and subsequently converting [12 a ] into [1] or pharmaceutically acceptable salts thereof. In accordance with another aspect of this invention, there are provided novel intermediates, inter alia the novel compounds [6 a ] and [12 a ]. The novel intermediates of the present invention are stable, solid compounds, obtainable in high yields, which can be easily purified by crystallization and stored for long periods of time.

FIELD OF THE INVENTION

The present invention relates to a novel process for the preparation ofdronedarone and pharmaceutically acceptable salts thereof, to novelintermediates used in this process and their preparation.

PRIOR ART

The following references are considered to be pertinent for the purposeof understanding the background of the present invention:

-   U.S. Pat. No. 5,223,510;-   H. R. Horton and D. E. Koshland, J. Methods in Enzymology, 1967, v.    11, 556;-   WO 01/28974 A2;-   WO 01/29019 A1; and-   U.S. Pat. No. 5,990,315.

BACKGROUND OF THE INVENTION

Dronedarone, SR 33589,N-[2-Butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-5-benzofuranyl]methanesulfonamide,having the formula [1]:

is a drug for the treatment of arrhythmia (U.S. Pat. No. 5,223,510).

A prior art method for preparing dronedarone [1], disclosed in U.S. Pat.No. 5,223,510, starts from 2-butyl-5-nitrobenzofuran according to thefollowing Scheme 1:

The starting material 2-butyl-5-nitrobenzofuran is prepared bymulti-stage processes, as showed in Scheme 2 (U.S. Pat. No. 5,223,510,H. R. Horton and D. E. Koshland, J. Methods in Enzymology, 1967, v. 11,556) and Scheme 3 (WO 01/28974 A2 and WO 01/29019 A1):

It is known that catalytic reduction of 2-butyl-5-nitrobenzofuran (3.4atm H₂/PtO₂/EtOH) gives 2-butyl-5-benzofuranamine free base, whichreacts with methanesulfonyl chloride in the presence of triethylamine asacid scavenger and carbon tetrachloride as a solvent to giveN-(2-butyl-5-benzofuranyl)-N-(methylsulfonyl)methanesulfonamide [14a]instead of N-(2-butyl-5-benzofuranyl)methanesulfonamide [14] (U.S. Pat.No. 5,223,510, Scheme 4):

Compound [14a] may be converted back to [14] but this necessitates theuse of larger amounts of methanesulfonyl chloride and of acid scavenger,thus causing increased costs. It also has to be noted that2-butyl-5-benzofuranamine free base is an unstable compound and can notbe stored for long periods of time.

SUMMARY OF INVENTION

It is an object of the present invention to provide a novel process forthe preparation of dronedarone and its pharmaceutically acceptablesalts, which is free of the above-mentioned disadvantages, starting withcommercially available materials and using simple reagents and low costsolvents, to afford high overall yield of the product.

The above object is achieved in accordance with the present inventionwhich, in one aspect thereof, provides a process for preparingdronedarone [1] and pharmaceutically acceptable salts thereof, startingwith commercially available materials such as p-anisidine orp-phenetidine. Thus, the process of the invention comprises the stepsof:

-   (a) reacting a compound of formula [3] with 2-bromohexanoyl chloride    or bromide in the presence of aluminum chloride or bromide to obtain    a compound of formula [6]:

wherein R¹ is methyl or ethyl; R² is selected from alkyl, aryl, aralkyl,alkoxy, aryloxy, and aralkoxy;

-   (b) converting the compound [6] obtained in step (a) above into the    compound of formula [9]:

without isolation of the intermediate compounds [7] or [8]:

wherein R² is as defined above;

-   (c) dehydrating and N-deprotecting the compound of formula [9]    obtained in step (b) above in aqueous solution of HX⁴, wherein HX⁴    is selected from hydrogen chloride, hydrogen bromide, sulfuric acid,    methanesulfonic acid and p-toluenesulfonic acid, to obtain the solid    salt of 2-butyl-5-benzofuranamine [12]

without isolation of the intermediate compounds [10] or [1]:

wherein R² is as defined above;

-   (d) optionally, preparing 2-butyl-5-benzofuranamine free base from    the acid addition salt of 2-butyl-5-benzofuranamine [12] obtained in    step (c) above;-   (e) reacting the 2-butyl-5-benzofuranamine free base obtained in    step (d) above or the acid addition salt of    2-butyl-5-benzofuranamine [12] obtained in step (c) with an agent    selected from methanesulfonic anhydride and methanesulfonyl chloride    or fluoride to obtain N-(2-butyl-5-benzofuranyl)methanesulfonamide    [14]

-   (f) Friedel-Crafts acylating the compound [14] obtained in step (e)    above with 4-(3-dibutylaminopropoxy)benzoyl chloride hydrochloride    [15]

to obtain dronedarone [1] or a pharmaceutically acceptable salt thereof.

According to a preferred embodiment, the present invention provides aprocess for preparing dronedarone [1] and pharmaceutically acceptablesalts thereof, which comprises N-acetylating of p-anisidine orp-phenetidine with acetic anhydride, reacting of the obtainedN-(4-alkoxyphenyl)acetamide with 2-bromohexanoyl chloride or bromide inthe presence of aluminum chloride or bromide to obtainN-[3-(2-bromohexanoyl)-4-hydroxyphenyl]acetamide [6a], converting thecompound [6a] into 2-butyl-5-benzofuranamine hydrochloride [12a] andsubsequently converting [12a] into [1] or pharmaceutically acceptablesalts thereof.

The intermediates [6], [9], [10] and the acid addition salts of2-butyl-5-benzofuranamine [12] are new compounds and constitute anotheraspect of the present invention. The novel intermediates of the presentinvention are obtained in stable, solid form. In addition, they areobtained in high yields, may be easily purified by crystallization andstored for long periods of time.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of formula [3] may be prepared by methods known in the art, byreacting p-anisidine or p-phenetidine with compounds of formula [2]:R²COX¹  [2]wherein R² is selected from alkyl, aryl, aralkyl, alkoxy, aryloxy andaralkoxy and X¹ is R²COO—, chlorine or bromine.

The reaction of [3] with 2-bromohexanoyl chloride or bromide is carriedout under Friedel-Crafts reaction conditions using more than oneequivalent of aluminum chloride or bromide as Lewis acid catalyst andO-deprotecting reagent. Preferably, from 2 to 4 moles of aluminumchloride or bromide are used with 1 mole of compound [3]. Preferably,the reaction is carried out in the presence of nitroalkane ornitroarene—chelating agents increasing the solubility of aluminumcompounds and improving the yields of the reaction. Preparation ofcompound [6] from p-anisidine or p-phenetidine is depicted in Scheme 5:

wherein R¹ is methyl or ethyl; R² is selected from alkyl, aryl, aralkyl,alkoxy, aryloxy or aralkoxy; X¹ is R²COO—, chlorine or bromine; X² ischlorine or bromine and X³′ is chlorine or bromine.

Preferably, compound [6] is converted to compound [12] without isolatingthe intermediate compounds [7-11] using the “one pot” process depictedin Scheme 6:

wherein R² is selected from alkyl, aryl, aralkyl, alkoxy, aryloxy andaralkoxy and HX⁴ is selected from hydrogen chloride, hydrogen bromide,sulfuric acid, methanesulfonic acid or p-toluenesulfonic acid.

It should be noted that each step of the above process may besuccessfully carried out as individual reaction steps and all thecompounds [8-11], except for the unstable compound [7], may be isolatedand used as precursors for the preparation of compound [12]. Compounds[6], [9], [10] and [12] are stable, solid compounds which can be easilypurified by crystallization and stored for long periods of time.

Preferably, the reductions according to Scheme 6 are carried out in thepresence of sodium borohydride as reductive agent. Preferably, the baseaccording to Scheme 6 is a metal bicarbonate or acetate. Preferably R²is methyl and R²COX¹ in this case is acetic anhydride. HX⁴ is preferablyHCl.

Preferably, the process for the preparation of dronedarone [1] orpharmaceutically acceptable salts thereof according to the presentinvention includes the steps of:

-   (a) N-acetylating p-anisidine or p-phenetidine with acetic anhydride    and reacting the obtained N-(4-alkoxyphenyl)acetamide with    2-bromohexanoyl chloride or bromide in the presence of aluminum    chloride or bromide to form    N-[3-(2-bromohexanoyl)-4-hydroxyphenyl]acetamide [6a];-   (b) converting the compound [6a] obtained in step (a) above into    2-butyl-5-benzofuranamine hydrochloride [12a] by “one-pot”    procedure;-   (c) optionally, preparing 2-butyl-5-benzofuranamine free base from    2-butyl-5-benzofuranamine hydrochloride [12a] obtained in step (b)    above;-   (d) reacting the 2-butyl-5-benzofuranamine free base obtained in    step (c) above or 2-butyl-5-benzofuranamine hydrochloride [12a]    obtained in step (b) with methanesulfonyl chloride without addition    any other acid scavenger to obtain    N-(2-butyl-5-benzofuranyl)methanesulfonamide [14]:

-   (e) Friedel-Crafts acylating of    N-(2-butyl-5-benzofuranyl)methanesulfonamide [14] obtained in    step (d) above with 4-(3-dibutylaminopropoxy)benzoyl chloride    hydrochloride [15] to obtain dronedarone [1] or a pharmaceutically    acceptable salt thereof:

The above process is showed in the following Schemes 7 and 8.

The compound [12a] may be converted into dronedarone [1] by the methoddepicted in Scheme 8 below:

wherein X⁵ is selected from chlorine, fluorine and methanesulfonylgroup. X⁵ is preferably chlorine.

In the preparation of N-(2-butyl-5-benzofuranyl)methanesulfonamide [14]it is difficult to drive the conversion of 2-butyl-5-benzofuranamine tocompletion in the presence of a base without the formation of asubstantial quantity ofN-(2-butyl-5-benzofuranyl)-N-(methylsulfonyl)methanesulfonamide [14a].In order to optimize the conversion of 2-butyl-5-benzofuranamine to thedesired compound [14] it is necessary to stop the reaction when onlypartial convertion of the aryl amine has been achieved. This leads toreduced yields which can be compensated for by additional processing torecover 2-butyl-5-benzofuranamine. Alternatively, the reaction can bedriven to completion in the presence of a base and the co-product [14a]converted back to the secondary sulfonamide [14]. The reaction of2-butyl-5-benzofuranamine or its salt with methanesulfonyl chloride canbe carried out according to a procedure described in U.S. Pat. No.5,990,315.

Preferably the catalyst in the Friedel-Crafts acylation ofN-(2-butyl-5-benzofuranyl)methanesulfonamide [14] is a Lewis acid.Preferably the Lewis acid is tin (IV) chloride.

4-(3-Dibutylaminopropoxy)benzoyl chloride hydrochloride [15] is obtainedfrom compound 1161 according to Scheme 9:

R³ is an alkyl group, and preferably methyl.

The compound [19] is preferably prepared by a “one-pot” procedure fromcompound [16] without isolating the intermediate compounds [17] and[18].

This invention will be better understood from the Examples that follow.However, the examples illustrate, but do not limit, the invention. Thoseskilled in the art will readily appreciate that the specific methods andresults discussed are merely illustrative of the invention as describedand claimed in the claims that follow thereafter.

EXAMPLES Example 1

Acetic anhydride (10.21 g, 9.4 mL, 100 mmol) was added dropwise over 1hour to a stirred solution of p-anisidine (12.32 g, 100 mmol) indichloromethane (40 mL) at 25-30° C. The mixture was stirred for anadditional 1 hour at the same temperature. Hexane (120 mL) was addeddropwise to the mixture at 25-30° C. The obtained suspension was stirredfor 1 hour at the same temperature. The precipitated crystals wereseparated by filtration and dried under reduced pressure to give 15.31 g(92.7%) of N-(4-methoxyphenyl)acetamide [3a] as off-white crystals.

¹H NMR (CDCl₃): 7.84 (bs, 1H), 7.35 (m, 2H), 6.79 (m, 2H), 3.74 (s, 3H),2.08 (s, 3H).

Example 2

Aluminium chloride (20.00 g, 150 mmol) was carefully added to a stirredsolution of N-(4-methoxyphenyl)acetamide [3a] (8.26 g, 50.0 mmol) indichloromethane (30 mL) at 0-5° C. (ice/water bath). Nitromethane (8.2mL, 150 mmol) was added to the mixture in one portion. A solution of2-bromohexanoyl chloride (12.81 g, 60.0 mmol) in dichloromethane (20 mL)was added dropwise to the stirred mixture at room temperature. Theobtained mixture was stirred for 4 hours at the same temperature.Aluminum chloride (6.67 g, 50.0 mmol) was added in one portion to thestirred mixture at room temperature. The mixture was stirred overnightat the same temperature. The mixture was carefully poured into ice/watermixture. The mixture was extracted with ethyl acetate (150 mL then 2×50mL). The combined organic layers were washed with brine (50 mL), driedover sodium sulfate, filtered and evaporated under reduced pressure at50° C. (water bath). The residue (21.20 g) was stirred with hexane (150mL) for 1 hour at room temperature. The precipitated solids werefiltered off, washed on the filter with hexane and dried at 50° C.(water bath) to the constant weight to give 15.03 g (91.6%) ofN-[3-(2-bromohexanoyl)-4-hydroxyphenyl]acetamide [6a] as yellow crystalswith mp 137-138° C. (toluene).

¹H NMR (CDCl₃): 11.79 (s, 1H), 8.16 (d, J=2.2 Hz, 1H), 7.39 (dd, J=8.6and 2.2 Hz, 1H), 7.38 (bs, 1H), 6.95 (d, J=8.6 Hz, 1H), 5.11 (t, J=7.0Hz, 1H), 2.16 (s, 3H), 2.11 (m, 2H), 1.36 (m, 4H), 0.90 (t, J=7.2 Hz,3H).

Example 3

Sodium bicarbonate (3.36 g, 40.0 mmol) was added in several portions toa stirred boiling mixture ofN-[3-(2-bromohexanoyl)-4-hydroxyphenyl]acetamide [6a] (13.13 g, 40.0mmol) and methanol (30 mL). The mixture was stirred under refluxconditions for 2 hour. Sodium borohydride (1.51 g, 40.0 mmol) was addedin several portions to the mixture at 0-5° C. (ice/water bath). Themixture was stirred for 30 min at the same temperature and 15%hydrochloric acid (100 mL) was added. The solution was stirred for 4hours under reflux conditions and for 1 hour at 0-5° C. (ice/waterbath). The precipitated crystals were filtered off, washed on the filterwith water (20 mL) and ethyl acetate (20 mL) and dried to give 7.62 g(84.5% yield from 3 steps) of 2-butyl-5-benzofuranamine hydrochloride[12a] as off-white crystals with mp 190-193° C. (dec.).

¹H NMR (CDCl₃): 7.52 (s, 1H), 7.18 (s, 2H), 6.19 (s, 1H), 2.67 (t, J=7.2Hz, 2H), 1.65 (m, 2H), 1.39 (m, 2H), 0.92 (t, J=7.2 Hz, 3H).

Example 4

A mixture of N-[3-(2-bromohexanoyl)-4-hydroxyphenyl]acetamide [6a] (3.28g, 10.0 mmol), sodium bicarbonate (0.84 g, 10.0 mmol) and methanol (30mL) was stirred under reflux conditions for 2 hours. Sodium borohydride(0.76 g, 20.0 mmol) was added in several portions to the mixture at 0-5°C. (ice/water bath). The mixture was stirred for 1 hour at the sametemperature. Methanol (20 mL) was evaporated from the mixture and water(100 mL) was added to the residue. The obtained mixture was stirred for1 hour at 0-5° C. (ice/water bath). The precipitated crystals werefiltered and dried under reduced pressure at 50-60° C. to give 2.01 g(80.6% yield from 2 steps) ofN-(2-butyl-3-hydroxy-2,3-dihydro-5-benzofuranyl)acetamide [9a] asoff-white crystals with mp 134-137° C.

¹H NMR (CDCl₃): 7.59 (bs, 1H), 7.48 (m, 1H), 7.13 (m, 1H), 6.69 (m, 1H),4.89 (dd, J=13.3 and 5.5 Hz, 1H), 4.40 (m, 1H), 2.07 (s, 3H), 1.81 (m,2H), 1.46 (m, 5H), 0.93 (t, J=7.0 Hz, 3H).

Example 5

A mixture of N-(2-butyl-3-hydroxy-2,3-dihydro-5-benzofuranyl)acetamide[9a] (2.50 g, 10.0 mmol), p-toluenesulfonic acid monohydrate (0.19 g,1.0 mmol) and dichloromethane (30 mL) was stirred for 1 hour at roomtemperature and passed through short silica gel column. The column waswashed with dichloromethane (300 mL). The solvent was evaporated underreduced pressure to give 2.11 g (91.3%) ofN-(2-butyl-5-benzofuranyl)acetamide [10a] as off-white crystals with mp71-73° C.

¹H NMR (CDCl₃): 8.07 (bs, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.24 (d, J=8.0Hz, 1H), 7.11 (dd, J=8.0 and 2.0 Hz, 1H), 6.24 (s, 1H), 2.70 (t, J=7.0Hz, 2H), 2.10 (s, 3H), 1.67 (m, 2H), 1.41 (m, 2H), 0.92 (t, J=7.0 Hz,3H).

Example 6

2-Butyl-5-benzofuranamine hydrochloride [12a]

A mixture of N-(2-butyl-5-benzofuranyl)acetamide [10a] (1.16 g, 5.0mmol) and 15% hydrochloric acid (10 mL) was stirred overnight underreflux conditions and 2 hours at 0-5° C. The precipitated crystals werefiltered off, washed on the filter with cold water and ethyl acetate anddried under reduced pressure at 50° C. (water bath) to a constant weightto give 1.00 g (88.6%) of 2-butyl-5-benzofuranamine hydrochloride [12a]as off-white crystalls with mp 189-192° C. (with decomposition).

Example 7

Methanesulfonyl chloride (0.92 g, 0.6 mL, 8.0 mmol) was added dropwiseto a stirred boiling mixture of 2-butyl-5-benzofuranylaminehydrochloride [12a] (0.90 g, 4.0 mmol), tetramethylammonium chloride(0.11 g, 1.0 mmol) and toluene (10 mL) for 1 hour. The mixture wasstirred under reflux conditions for 1 hour. Ethyl acetate (20 mL) andwater (30 mL) were added to the cold mixture. The organic layer wasseparated and aqueous layer was extracted with ethyl acetate (2×20 mL).The combined organic layers were dried over sodium sulfate andevaporated under reduced pressure to give 1.01 g (94.0%) ofN-(2-butyl-5-benzofuranyl)methanesulfonamide [14] with mp 104.9-105.9°C.

¹H NMR (CDCl₃): 7.40 (d, J=2.2 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.05(dd, J=8.6 and 2.2 Hz, 1H), 6.63 (s, 1H), 6.34 (s, 1H), 2.95 (s, 3H),2.74 (t, J=7.2 Hz, 2H), 1.71 (m, 2H), 1.39 (m, 2H), 0.93 (t, J=7.2 Hz,3H).

Example 8

A mixture of 2-butyl-5-benzofuranamine hydrochloride [12a] (3.16 g, 14.0mmol) and toluene (30 mL) and a solution of sodium hydroxide (0.6 g,15.0 mmol) in water (30 mL) were stirred for 0.5 hour at roomtemperature. The organic layer was separated and the aqueous layer wasextracted with toluene (2×30 mL). The combined organic layers were driedover sodium sulfate, filtered and concentrated to the volume of 30 mL.

A solution of methanesulfonyl chloride (1.98 g, 17.2 mmol, 1.3 equiv.)in toluene (10 mL) was added dropwise over period of 1 hour to thestirred boiling mixture. The mixture was stirred for 2 hour under refluxconditions. Hexane (40 mL) was added to the mixture at room temperature.The obtained suspension was stirred for 0.5 hour at 0-5° C. (ice/waterbath). The precipitated crystals were filtered and dissolved indichloromethane (30 mL). The solution was filtered through short silicagel column (5 g). The column was washed with dichloromethane andcombined filtrates were evaporated under reduced pressure at 50-60° C.(water bath) to give 3.41 g (91.0%) ofN-(2-butyl-5-benzofuranyl)methanesulfonamide [14] (one spot on TLC).

Example 9

Tin (IV) chloride (2.7 mL, 23.0 mmol) was added dropwise to a stirredsolution of N-(2-butyl-5-benzofuranyl)methanesulfonamide [14] (2.50 g,9.4 mmol) and 4-(3-dibutylaminopropoxy)benzoyl chloride hydrochloride[15] (3.62 g, 10.0 mmol) in dichloromethane (20 mL) at 0-5° C. Themixture was stirred for 30 min at the same temperature and for 2 hoursat room temperature. Water (50 mL) was added dropwise to the stirredmixture at 0-5° C. The mixture was extracted with dichloromethane (3×30mL). The combined organic layers were washed with saturated sodiumbicarbonate aqueous solution, dried over sodium sulfate and evaporated.3.45 g (65.9%) of dronedarone [1] was obtained after purification of theresidue by column chromatography on silica gel (ethyl acetate/hexane 1:3v/v).

¹H NMR (CDCl₃): 7.77 (d, J=8.5 Hz, 2H), 7.27 (m, 3H), 6.91 (d, J=8.5 Hz,2H), 5.52 (bs, 1H), 4.05 (t, J=6.0 Hz, 2H), 2.87 (s, 3H), 2.79 (t, J=7.0Hz, 2H), 2.57 (t, J=7.0 Hz, 2H), 2.39 (t, J=7.0 Hz, 4H), 1.90 (m, 2H),1.68 (m, 2H), 1.33 (m, 10H), 0.82 (m, 9H).

Example 10

Hydrogen chloride, 10% solution in ethyl acetate (2.5 mL, 7.00 mmol),was added dropwise to a stirred solution of dronedarone (3.40 g, 6.00mmol) in ethyl acetate (30 mL) at 0-5° C. (ice/water bath). The mixturewas stirred for 1 hour at the same temperature and evaporated underreduced pressure at 50-60° C. (water bath) to give dronedaronehydrochloride [1a].

¹H NMR (CDCl₃): 11.56 (bs, 1H), 8.18 (s, 1H), 7.72 (d, J=8.5 Hz, 2H),7.27 (m, 3H), 6.87 (d, J=8.5 Hz, 2H), 4.15 (m, 2H), 3.23 (m, 2H), 3.03(m, 5H), 2.86 (s, 3H), 2.37 (m, 2H), 2.00 (m, 1H), 1.74 (m, 6H), 1.33(m, 6H), 0.88 (m, 9H).

Example 11

A mixture of methyl 4-hydroxybenzoate [16a] g, 150 mmol), potassiumcarbonate (41.49 g, 300 mmol), 1,3-dibromopropane (170.00 g, 842 mmol)and methyl ethyl ketone (MEK) (200 mL) were stirred under refluxconditions for 6 hours. The cold mixture was filtered off and solids onthe filter was washed with MEK (100 mL). The combined filtrates wereevaporated under reduced pressure at 90° C. to give the mixture ofmethyl 4-(3-bromopropoxy)benzoate and dimethyl4,4′-[1,3-propanediylbis(oxy)]bisbenzoate (41.00 g). Analytical samplesof methyl 4-(3-bromopropoxy)benzoate [17a] methyl4,4′-[1,3-propanediylbis(oxy)]bisbenzoate [20] isolated from the mixtureby column chromatography on silica gel. Methyl4-(3-bromopropoxy)benzoate [17a] ¹H NMR (CDCl₃): 7.95 (d, J=8.8 Hz, 2H),6.88 (d, J=8.8 Hz, 2H), 4.11 (t, J=7.0 Hz, 2H), 3.84 (s, 3H), 3.56 (t,J=7.0 Hz, 2H), 2.29 (m, 2H). Dimethyl4,4′-[1,3-propanediylbis(oxy)]bisbenzoate [20] ¹H NMR (CDCl₃): 7.96 (d,J=8.8 Hz, 4H), 6.90 (d, J=8.8 Hz, 4H), 4.20 (t, J=7.0 Hz, 4H), 3.86 (s,6H), 2.28 (m, 2H).

A solution of the mixture of methyl 4-(3-bromopropoxy)benzoate [17a]methyl 4,4′-[1,3-propanediylbis(oxy)]bisbenzoate [20] previous step(19.12 g) and dibutylamine (27.14 g, 35.7 mL, 210 mmol) in toluene (50.0mL) was stirred under reflux conditions for 3 hours, cooled andextracted with 15% hydrochloric acid (3×40 mL). The combined aqueouslayers were washed with of toluene (50 mL), basified to pH 8.5 withsodium bicarbonate and extracted with toluene (3×30 mL). The combinedorganic layers were dried over sodium sulfate, filtered and evaporatedunder reduced pressure at 60° C. (water bath). The residue was dissolvedin hexane and passed through thin layer of silica gel. The solvent wasevaporated under reduced pressure at 50-60° C. (water bath) to give14.71 g (61.1% yield from 2 steps) of methyl4-(3-dibutylaminopropoxy)benzoate [18a] as an oil.

¹H NMR (CDCl₃): 7.95 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 4.04 (t,J=7.0 Hz, 2H), 3.85 (s, 3H), 2.55 (t, J=7.0 Hz, 2H), 2.38 (t, J=7.0 Hz,4H), 1.86 (m, 2H), 1.34 (m, 8H), 0.86 (t, J=7.0 Hz, 6H).

Example 12

A mixture of methyl 4-(3-dibutylaminopropoxy)benzoate [18a] (7.65 g,23.8 mmol) and 32% hydrochloric acid (30 mL) was stirred for 5 hoursunder reflux conditions and for one hour at 0-5° C. (ice/water bath).The suspension was filtered. The precipitated crystals were washed onthe filter with water and hexane and dried under reduced pressure at50-60° C. (water bath) to give 6.90 g (85.7%) of4-(3-dibutylaminopropoxy)benzoic acid hydrochloride [19a] as whitecrystals with mp 157-159° C.

¹H NMR (CDCl₃): 11.75 (bs, 1H), 7.93 (d, J=8.7 Hz, 2H), 6.80 (d, J=8.7Hz, 2H), 4.09 (m, 2H), 3.24 (m, 2H), 3.02 (m, 4H), 2.37 (m, 2H), 1.78(m, 4H), 1.36 (m, 4H), 0.93 (t, J=7.2 Hz, 6H).

Example 13

A mixture of 4-(3-dibutylaminopropoxy)benzoic acid hydrochloride [19a](3.44 g, 10.0 mmol), thionyl chloride (5.87 g, 3.6 mL, 49.4 mmol) anddichloromethane (10 mL) was stirred under reflux conditions for 1 hourand evaporated under reduced pressure at 60-70° C. (water bath) to give3.62 g (100% yield) of 4-(3-dibutylaminopropoxy)benzoyl chloridehydrochloride [15].

1. A process for preparing dronedarone [1]

or a pharmaceutically acceptable salt thereof, which process comprisesthe steps of: (a) reacting a compound of formula [3] with2-bromohexanoyl chloride or bromide in the presence of aluminum chlorideor bromide to obtain a compound of formula [6]:

wherein R¹ is methyl or ethyl; and R² is selected from the groupconsisting of alkyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy; (b)converting the compound [6] obtained in step (a) above into the compoundof formula [9]

(c) dehydrating and N-deprotecting the compound of formula [9] obtainedin step (b) above in an aqueous solution of HX⁴, wherein HX⁴ is selectedfrom the group consisting of hydrogen chloride, hydrogen bromide,sulfuric acid, methanesulfonic acid and p-toluenesulfonic acid, toobtain the solid acid addition salt of 2-butyl-5-benzofuranamine [12]

(d) optionally, preparing 2-butyl-5-benzofuranamine free base from theacid addition salt of 2-butyl-5-benzofuranamine [12] obtained in step(c) above; (e) reacting the 2-butyl-5-benzofuranamine free base obtainedin step (d) above or the acid addition salt of 2-butyl-5-benzofuranamine[12] obtained in step (c) with an agent selected from the groupconsisting of methanesulfonic anhydride and methanesulfonyl chloride orfluoride to obtain N- (2-butyl-5-benzofuranyl)methanesulfonamide [14]

(f) Friedel-Crafts acylating of N(2-butyl-5-benzofuranyl)methanesulfonamide [14] obtained in step (e)above with 4- (3-dibutylaminopropoxy)benzoyl chloride hydrochloride [15]

to obtain dronedarone [1] or a pharmaceutically acceptable salt thereof.2. The process of claim 1 wherein compound 6 is converted into thecompound of formula [9] in step (b) without isolating the intermediatecompounds [7] and [8]:


3. The process of claim 1 wherein compound [12] is obtained in step (c)without isolating the intermediate compounds [10] and [11]:


4. The process of claim 1, wherein R² is a methyl group.
 5. The processof claim 1, wherein HX⁴ is hydrogen chloride.
 6. A compound of formula[6]:

wherein R² is selected from the group consisting of alkyl, aryl,aralkyl, alkoxy, aryloxy and aralkoxy.
 7. A compound of formula [7]:

wherein R² is selected from the group consisting of alkyl, aryl,aralkyl, alkoxy, aryloxy and aralkoxy.
 8. A compound of formula [9]:

wherein R² is selected from the group consisting of alkyl, aryl,aralkyl, alkoxy, aryloxy and aralkoxy.
 9. A compound of formula [10]:

wherein R² is selected from the group consisting of alkyl, aryl,aralkyl, alkoxy, aryloxy and aralkoxy.
 10. The compound of claim 6wherein R² is methyl.
 11. The compound of claim 7 wherein R² is methyl.12. The compound of claim 8 wherein R² is methyl.
 13. The compound ofclaim 9 wherein R² is methyl.
 14. A process according to claim 1 for thepreparation of dronedarone [1] or apharmaceutically acceptable saltthereof:

such process comprising the steps of: N-acetylating of p-anisidine orp-phenetidine with acetic anhydride, reacting of the obtainedN-(4-alkoxyphenyl)acetamide with 2-bromohexanoyl chloride or bromide inthe presence of aluminum chloride or bromide to obtainN-[3-(2-bromohexanoyl)-4-hydroxyphenyl] acetamide [6a], converting thecompound [6] into 2-butyl-5-benzofuranamine hydrochloride [12a] andsubsequently converting [12a] into [1] or a pharmaceutically acceptablesalt thereof.
 15. A compound of formula [6]: